In this program-project we propose to investigate the areas believed to be the most promising for providing an integrated synthesis of the fundamental mechanisms of hypertension. We regard the following constellation of factors: 1) renal humoral agents and renal handling of Na, 2) body Na, ECF and blood volume, and 3) cardiac output, as an interrelated axis affecting 4) the caliber of peripheral resistance vessels in normotension and hypertension. All projects will attempt to gain more knowledge concerning this constellation. The intrarenal concentrations of prostaglandins E2 and F2 alpha, (PGE2 and PGF2 alpha) will be studied in both Japanese and Milanese SHR rats and in "post- salt" hypertensive rats and with low Na diets. Renal PGE and PGF will also be studied in relation to Goldblatt hypertension and Cd-induced hypertension. The effects of hydrostatic pressure, O2 tension, Na concentration, osmolality, angiotensin, bradykinin, and norepinephrine on PGE2 and PGF2 alpha release from papilla halves in vitro will also be studied. The effect of varying inflow pressures will be studied and compared in isolated kidneys from normotensive nd hypertensive rats with regard to: a) urine Na and urine volume, b) blood flow, c) renin release, d) Na handling in proximal and distal tubules and collecting duct, e) urinary kallikrein, f) intrarenal PGE2 and PGF2 alpha. Micropuncture of the kidney will be used to investigate single-nephron vascular pressures, flows, and resistances in hypertensive rats, proximal and distal tubular effects of PGE2 and angiotensin, exaggerated natriuresis and pressure natriuresis in hypertension, and vascular effects of endogenous angiotensin. The influence of endogenous prostaglandins and angiotensin on the renal and mesenteric vascular beds in 2-kidney Goldblatt hypertension will be studied. Autoregulation of flow and venous capacitance in the forearm vascular bed of normotensive and hypertensive human subjects will be investigated in various states of Na balance and with various antihypertensive drugs. Cardiac output responses in rats either sensitive and resistant to Na Cl hypertension will be examined before and after high NaCl feeding.